The development of an efficacious vaccine to prevent infection by HIV has become an essential priority. The vast majority of cases of HIV infection to date have resulted from exposure to the virus during heterosexual or homosexual intercourse, with transmission of the virus occurring across mucosal surfaces. A primary challenge confronting HIV vaccine development efforts is the successful interruption of viral transmission through the effective induction of mucosal immune responses. Unfortunately, most candidate HIV vaccines preferentially induce systemic but not mucosal immune responses and are unlikely to prevent infection occurring via the most common routes of exposure. The basic hypothesis of this grant is that essential requirements for protective immunization against HIV and other related lentiviruses involve 1) induction of mucosal immunity and 2) immunological responses against multiple viral antigens. To this end, we have developed replication-competent poliovirus recombinants that can carry and express antigens derived from HIV and the simian immunodeficiency virus (SIV). This method permits the expression of SIV antigens at local mucosal sites. Infection of susceptible mice and cynomolgus monkeys with poliovirus recombinants elicits serum and secretory humoral responses, as well as a strong cellular immunity to the SIV sequences. Important advantages of the oral poliovirus vaccine include its ability to induce mucosal immunity, and its safety, affordability and documented efficacy in both developed and developing nations. In these studies, recombinant live-attenuated polioviruses that express SIV antigens will be used to inoculate susceptible mice and cynomolgus monkeys, and their ability to elicit both cellular and secretory immune responses on mucosal surfaces will be evaluated. Should the recombinant picornavirus elicit strong mucosal immune responses in monkeys, vaccinated animals will be challenged by instillation of virulent SIV onto the vaginal mucosa. Knowledge gained from these studies may productively add to our understanding of genital mucosal immunity in primates, the mucosal immune response to SIV antigens and, most importantly, to ongoing efforts to contain the AIDS pandemic through the development of an effective vaccine to prevent HIV transmission.